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Safety Profile Giuseppe Naso Sapienza Università di Roma
Associate Professor of Medical Oncology Head of Traslational Oncology -Breast Unit- Sapienza Università di Roma
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Compared with conventional paclitaxel, nab-paclitaxel
Proposed Mechanisms Behind the Higher Tumor Uptake and Greater Tumor Selectivity of nab-Paclitaxel Compared With Conventional Paclitaxel1,2 Compared with conventional paclitaxel, nab-paclitaxel 1. Reaches higher plasma concentrations of free paclitaxel3 2. Takes greater advantage of transcytosis to reach higher concentrations in the tumor interstitium1,4 3. Interacts with SPARC, via albumin, increasing nab-paclitaxel concentration in the tumor interstitium5 Desai et al. Clin Cancer Res. 2006;12(4): Scheff. Community Oncol. 2008;5(7 suppl 8):7-13. Gardner et al. Clin Cancer Res. 2008;14(13): Kratz et al. J Control Release. 2008;132(3): Desai et al. Transl Oncol. 2009;2(2):59-64. SPARC, secreted protein acidic and rich in cysteine.
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nab-Paclitaxel Concentrates in Tumors in Mice1
Mouse tumour model 1 min after iv injection Imaged tumor Fluorescently-labeled nab-paclitaxel is injected 15 min after iv injection References Drug delivery report 2007; data on file. †Nab-paclitaxel containing 0.3% fluorescent marker Imaging under Hg-lamp with 500–550 nm bandpass excitation 1. Data on file.
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nab-Paclitaxel Demonstrates Greater Tumor Selectivity1,2
nab-Paclitaxel demonstrates greater tumor selectivity compared with conventional paclitaxel in this preclinical model1,2 1.5 nab®-Paclitaxel > Conv paclitaxel 1.0 nab®-Paclitaxel = Conv paclitaxel Relative concentration (nab-Paclitaxel/Conventional paclitaxel) nab®-Paclitaxel < Conv paclitaxel 0.5 Normal tissues Tumor Blood Comparative tissue distribution (ratio) of radiolabeled drug in mice bearing human breast tumor xenografts 1 hour after dose.1,2 conv, conventional. Hawkins et al. AACR Poster 1189. Scheff . Community Oncol. 2008;5(7 suppl 8):7-13.
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nab-Paclitaxel Demonstrates Greater Tumor Selectivity1,2
nab-Paclitaxel demonstrates greater tumor selectivity compared with conventional paclitaxel in this preclinical model1,2 1.5 nab-Paclitaxel > Conv paclitaxel 1.0 = nab-Paclitaxel Conv paclitaxel Relative concentration (nab-Paclitaxel/Conventional paclitaxel) < nab-Paclitaxel Conv paclitaxel 0.5 Tumor Muscle Heart Kidney Lung Spleen Blood Comparative tissue distribution (ratio) of radiolabeled drug in mice bearing human breast tumor xenografts 1 hour after dose.1,2 Hawkins et al. AACR Poster 1189. Scheff . Community Oncol. 2008;5(7 suppl 8):7-13.
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Safety nab-Paclitaxel’s safety profile is well-characterized and manageable across multiple tumor types Gradishar WJ et al. J Clin Oncol. 2005;23: Socinski MA et al. J Clin Oncol. 2012;30: Hersh E, et al. Pigment Cell Melanoma Res. 2012;25: 863. Abstract. Von Hoff DD, et al. J Clin Oncol. 2013;31(No 4_suppl) [abstract LBA 148].
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NAB-paclitaxel: lo studio randomizzato di Fase III CA 012
52 16 MA 1219 :46:51 PM ESA 1256 :05:26 PM 69 21 NAB-paclitaxel: lo studio randomizzato di Fase III CA 012 Gradishar WJ, et al. J Clin Oncol. 2005;23(31):
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Profilo di sicurezza con NAB-paclitaxel rispetto a paclitaxel convenzionale (Breast Cancer)
Selected adverse events, % NAB-Paclitaxel 260 mg/m2 q3w (n = 226) Conv paclitaxel 175 mg/m2 q3w (n = 222) P value Grade 3 Grade 4 Hematologic Neutropenia Thrombocytopenia Anemia Febrile neutropenia 25 < 1 9 32 22 < .001 NS Non-hematologic Sensory neuropathy Fatigue Myalgia Vomiting Edema Hypersensitivity 10 8 7 3 2 1 .002 Median time to improvement of SN to grade ≤ 2 (days) 223 793 .0284 444 Grade 4 neutropenia was reported significantly more frequently in patients who received conventional paclitaxel compared with those receiving nab-paclitaxel (P < .001). No cases of grade 4 sensory neuropathy were reported in either treatment group; grade 3 sensory neuropathy occurred more often in the nab-paclitaxel arm compared with the conventional arm (P < .001). Patients in the nab-paclitaxel arm who experienced grade 3 sensory neuropathy improved to grade ≤ 2 in a median of 22 days. Table adapted from Davidson 20101 Davidson. EJC Supplements. 2010;8(1):11-18 Gradishar et al. J Clin Oncol. 2005;23(31): Cortes et al. EJC Supplements. 2010;8(1):1-10. Celgene Corporation. Data on file [CA 012 CSR]. conv, conventional; MBC, metastatic breast cancer; NS, not statistically significant; q3w, every 3 weeks; SN, sensory neuropathy. 8
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Rapido miglioramento della neuropatia sensoriale con NAB-paclitaxel
NAB-paclitaxel (n=24) + 1,00 0,75 0,50 0,25 0,00 + + Censurato + + 22 giorni (IC 95%), 17-22): tempo mediano di miglioramento con NAB-paclitaxel vs 79 giorni con paclitaxel convenzionale Percentuale di casi non risolti Although the incidence of neuropathy associated with nab-paclitaxel treatment was higher than that for the standard dose of paclitaxel (175 mg/m2), the median time to resolution of grade 3 neuropathy (to a lesser grade) was significantly less in the nab-paclitaxel group than in the paclitaxel group (22 days vs 79 days; P=0.03). Miglioramento dal grado 3 ai gradi 1 o 2 (giorni) Gradishar et al. J Clin Oncol 2005; 23: Reference Gradishar et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005;23:7794–7803
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Safety from CA046 (Metastatic Pancreatic Cancer)
Preferred Term nab-P + Gem n = 421 Gem n = 402 Patients with at least 1 AE leading to death, % 4 Grade ≥ 3 hematologic AEs,a % Neutropenia Leukopenia Thrombocytopenia Anemia 38 31 13 27 16 9 12 Patients who received growth factors, % 26 15 Febrile neutropenia,b % 3 1 Grade ≥ 3 nonhematologic AEsb in > 5% of patients, % Fatigue Peripheral neuropathyc Diarrhea 17 6 7 < 1 Grade ≥ 3 neuropathy Time to onset in days, median Time to improvement by ≥ 1 grade in days, median Time to improvement to grade ≤ 1 in days, median Patients who resumed nab-P, % 140 21 29 44 113 — Von Hoff DD, et al. J Clin Oncol. 2013;31(No 4_suppl) [abstract LBA 148]. a Based on lab values. b Based on investigator assessment of treatment-related events. c Grouped term.
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Safety from CA031 (Advanced NSCLC)
Adverse Event nab-P/C n = 514 sb-P/C n = 524 P Value Grade 3 4 Hematologic Abnormalities, Grade 3/4, % Neutropenia Thrombocytopenia Anemia Febrile neutropenia 33 13 22 < 1 14 5 32 7 6 1 26 2 < 0.001 NS Nonhematologic AEs, Grade 3/4, % Fatigue Sensory neuropathy Anorexia Nausea Myalgia Arthralgia 11 0.011 0.008 Time to improvement in grade ≥ 3 sensory neuropathy to grade 1 in days, median 38 104 — Socinski MA, et al. J Clin Oncol. 2012;30:
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Safety from CA033 (Metastatic Melanoma)
Grade ≥ 3 TRAE in ≥ 5% of Patients nab-Paclitaxel (n = 257) Dacarbazine (n = 258) Patients with ≥ 1 TRAE, % Patients with ≥ 1 Serious TRAE, % 50 9 28 7 Nonhematologic, %a Peripheral Neuropathyb Fatigue Alopecia 25 8 5 2 Hematologic, %a Neutropenia Leukopenia Lymphocytopenia Thrombocytopenia Anemia 20 12 10 11 6 Neuropathy, median days Time to Onset Time to Improvement by ≥ 1 grade Time to Improvement to grade ≤ 1 101 67 — a Except for lymphocytopenia, all events P < .05. b All but 2 neuropathy cases were grade 3. TRAE, treatment-related adverse event. Hersh E, et al. Pigment Cell Melanoma Res. 2012;25: 863. Abstract.
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Neurotossicità periferica
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Neurotoxicity resulting from axonal demyelination and swelling is also possibly an effect of Cr-EL.
Cyclosporine formulated with Cr-EL causes a similar neurotoxicity as opposed to oral formulations of cyclosporine [18], and docetaxel formulated with Tween 80 has a much lower incidence of neurotoxicity [19]. Finally, rats treated with Cr- EL-free paclitaxel showed no distribution of paclitaxel to the peripheral nervous system [20]. All the aforementioned limitations of formulating paclitaxel with Cr-EL prompted the development of novel formulations of paclitaxel.
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Neurotoxicity Following Repeated Cremophor EL Injections in Rats
Reference Authier et al. Assessment of neurotoxicity following repeated cremophor/ethanol injections in rats. Neurotox Res. 2001; 3: 301–306. Normal axons: ultra-thin section of fine sc nerve fibres from a control (saline) rat showing several normal axons Uranyl acetate and lead citrate (x 5000) Degenerated axons: ultra-thin section of fine sc nerve fibres from a Cremophor EL®-treated rat showing several degenerated axons Uranyl acetate and lead citrate (x 6000) Authier et al. Neurotox Res. 2001;3:301–306 Permission requested for re-use of picture. Authier et al. Neurotox Res. 2001;3:301–306.
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Grade 3 neuropathy improved more rapidly with nab-paclitaxel
1.00 Sensory neuropathy occurred with similar frequency in all study arms Rate of improvement was greater in all nab-paclitaxel arms vs. docetaxel Median time improvement of grade 3 neuropathy to ≤ grade 1: Nab-paclitaxel 300 mg/m2 q3w: 22 days Nab-paclitaxel 100 mg/m2 qw: 22 days Nab-paclitaxel 150 mg/m2 qw: 19 days Docetaxel 100 mg/m2 q3w: 37 days The long tail in the Abraxane 150 mg/m2 qw curve represents a single patient who recovered ~3 months after the event Gradishar et al. J Clin Oncol 2009;27: 18
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Safety In phase III trials, peripheral neuropathy from nab-paclitaxel was dose- and schedule-dependent, and dose modification typically led to improvement to grade ≤ 1 in 1 to 2 months Gradishar WJ et al. J Clin Oncol. 2005;23: Socinski MA et al. J Clin Oncol. 2012;30: Hersh E, et al. Pigment Cell Melanoma Res. 2012;25: 863. Abstract. Von Hoff DD, et al. J Clin Oncol. 2013;31(No 4_suppl) [abstract LBA 148]. Scheff RJ. Commun Oncol. 2008;5:7-13. Celgene data on file. CSR Trial CA012. Celgene data on file. Data table Cortes J, et al. EJC Supplements. 2010;8:1-10.
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San Antonio 2012 20
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Ciruelos E. et al. SABCS 2012
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Arruolamento iniziato nel dicembre 2012
Studio randomizzato in aperto di fase II in pazienti HER2 negative mai precedentemente trattate per la malattia metastatica Obiettivo dello studio: caratterizzare la neurotossicità in base al Total Neuropathy Score (TNS) e alle modifiche elettromiografiche Arruolamento iniziato nel dicembre 2012 Ciruelos E. et al. SABCS 2012
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San Antonio 2014
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Efficacy Tolerability
nab-paclitaxel achieves higher efficacy and favourable safety profile by leveraging the properties of albumin1-8 Clinical benefit Clinical benefit Implications Implications Tumour- targeted MoA Tumour- targeted MoA Efficacy Tolerability Abraxane [package insert]. Summit, NJ: Celgene Corporation; 2011. Scheff Community Oncologist. 2008;5(7 suppl 8):7-13. Desai et al. Clin Cancer Res. 2006;12: Schnitzer et al. J Biol Chem. 1994;269: Gradishar et al. J Clin Oncol. 2005;23: Sparreboom et al. Clin Cancer Res. 2005;11: Desai. Drug Delivery Report. 2008;Winter 2007/2008:35-41. Taxol [package insert]. Princeton, NJ: Bristol-Meyers Squibb; 2010. MoA: Meccanism Of Action
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Giuseppe Naso
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